【作者】 黄培；

【导师】 黄勋彬；

【作者基本信息】 华中科技大学 ， 妇产科学， 2016， 硕士

【摘要】 第一部分低剂量炔雌醇/左炔诺孕酮的临床疗效、依从性及耐受性研究目的:评估0.02 mg炔雌醇(ethinylestradiol,EE)/0.10 mg左炔诺孕酮(levonorgestrel,LNG)避孕的有效性、人群服药的依从性及耐受性。方法:选取愿意采取口服避孕药避孕的符合入选及排除标准的70例受试者,随机分为试验组(0.02 mg EE/0.10 mg LNG)52例和对照组(0.03 mg EE/0.15 mg LNG)18例。受试者在月经第1天开始服用第1片活性片,每天1片,28天为一个服药周期,共13个服药周期。自开始服药之日起受试者填写日记卡记录服药片数、不良事件、阴道流血情况等直至服药结束。受试者在服药前及服药后的第2、5、8、11个周期的前1~7天和完成第13个服药周期后的前1~7天来医院访视。结果:自2014.7.9-2016.3.1两组共完成516个服药周期,试验组370个周期,对照组146个周期,无一例妊娠,避孕效果好。试验组370个服药周期中有23个周期(6.22%)漏服≥1片活性片,3例受试者同一周期内连续漏服≥3片活性片。对照组146个服药周期中有13个服药周期(8.9%)漏服1~2片活性片,无受试者漏服≥3片活性片。自2014.7.9-2016.3.1有11人由于多种原因脱落。不良事件在试验组比对照组中的发生率低,其中腹胀组间比较有统计学差异(P<0.05),在前10个服药周期中,随着服药周期的延长两组的不良事件发生率均出现降低的趋势。结论:两种剂量的避孕药均有良好的避孕有效性及可接受性,0.02 mg EE/0.10 mg LNG组的不良事件发生率较低,人群的耐受性较好。第二部分评估低剂量炔雌醇/左炔诺孕酮的周期控制性及对经前期不适症状的影响目的:评估0.02 mg EE/0.10 mg LNG的周期控制性及对经前期不适症状的影响。方法:选取能顺利完成9个服药周期的人群36例(试验组25例,对照组11例),根据受试者的日记卡上记录的阴道流血情况一栏,初步评估0.02 mg EE/0.10 mg LNG在服药前后及与对照组相比随着服药周期的延长月经周期、月经持续时间和不规则出血率的变化。选取能顺利完成7个服药周期的人群48例(试验组34例,对照组14例),依据受试者填写的经期不适问卷(Menstrual discomfort questionnaire,MDQ)比较两组在服药前后及两组间MDQ评分的变化,初步评估0.02 mg EE/0.10 mg LNG对经前期不适症状的影响。结果:0.02 mg EE/0.10 mg LNG组在第2、8个服药周期的平均月经周期与服药前相比均缩短并有统计学差异(P<0.05),对照组无显著性差异。在第5个服药周期的月经持续时间对照组比试验组短且有统计学差异(P<0.05),但均在受试者可以接受的范围内,两组无一例发生闭经。试验组的点滴出血率是4.44%,对照组的是2.02%,两组随着服药周期的延长不规则出血率均降低,组间无统计学差异。两组的月经前MDQ总评分(除身心健康感一项)在服药后比服药前降低,但无统计学差异,服药后月经前注意力不集中指标的MDQ评分在对照组比试验组低且有统计学差异(P<0.05)。结论:两组均有良好的周期控制性,0.02 mg EE/0.10 mg LNG组的不规则出血率较高,但在受试者可以接受的范围内。两组在服药后对经前期不适症状无显著影响,0.03 mg EE/0.15 mg LNG组可能比0.02 mg EE/0.10 mg LNG组更好的改善经前期注意力不集中的症状。第三部分低剂量炔雌醇/左炔诺孕酮的安全性研究试验一评估低剂量炔雌醇/左炔诺孕酮对脂代谢及凝血功能的影响目的:评估0.02 mg EE/0.10 mg LNG对脂代谢及凝血功能的影响。方法:选取前述能顺利完成7个服药周期的受试者(试验组34例,对照组14例),在服药前和第8个服药周期时分别抽取空腹血检测凝血、血生化及血常规,体重、血压、心率在服药前及第2、5、8个服药周期的前7天内测量。结果:两组的体重指数、血压、心率、血常规及血生化指标在服药前后及组间相比均无统计学差异。在服药后两组的凝血酶原时间(Prothrombin time,PT)、部分活化凝血活酶时间(Activated partial thromboplastin time,APTT)均缩短,凝血酶时间(Thrombin time,TT)延长且有统计学差异(P<0.05)但均在正常范围内,组间比较无统计学差异。结论:服用0.02 mg EE/0.10 mg LNG 7个周期后不能有临床意义的影响脂代谢及凝血功能。试验二含有炔雌醇/左炔诺孕酮的避孕药对瘦素、脂联素的影响目的:分析含有EE/LNG的两种剂量的避孕药对瘦素(Leptin,LEP)、脂联素(Adiponectin,ADP)的影响及LEP、ADP分别与各个糖脂代谢指标间的相关性。方法:选取未采取避孕药避孕的健康女性28例作为未服药组,从前述能顺利完成前7个服药周期的人群中选取在同一月经周期时段访视的健康人群28例(服药组1有20例,服药组2有8例),抽取空腹血,应用酶联免疫吸附法(Enzyme-linked immunosorbent assay,ELISA)测定ADP与LEP的含量,脂代谢指标的测定同第三部分试验一。结果:ADP与TC、LDL、Castelli index I呈显著负相关。未服药组和服药组1、2两两之间比较后LEP、ADP及ADP/LEP均无统计学差异。结论:ADP参与调节脂代谢,服用含有EE/LNG的两种剂量的避孕药7个周期后不能显著影响LEP、ADP、ADP/LEP的水平,但需要扩大样本量、延长服药周期并控制干扰因素进一步评估服用含有EE/LNG的避孕药后对LEP、ADP的影响。更多还原

【Abstract】 Part I Efficacy, compliance and tolerance of the combined oral contraceptives containing lower dosage of Ethinylestradiol/LevonorgestrelObjectives: To evaluate contraceptive efficacy, compliance and tolerance of the 0.02 mg EE/0.10 mg LNG.Methods: A total of 70 subjects who were conformed to the inclusion and exclusion criteria and willing to take the oral contraceptive pills were evaluated. They were random Ly divided into the test group(0.02 mg EE/0.10 mg LNG) and the control group(0.03 mg EE/0.15 mg LNG), which contained 52 cases and 18 cases respectively.The oral contraceptives was administered at the first day of the menstrual cycle and once a day for 21 days, followed by 7 days of placebo for a complete cycle. All participants would complete 13 cycles. Each woman completed a daily diary that included the number of drugs, side effects and vaginal bleeding when each pill was taken.Subjects were asked to visit at 2, 5, 8, 11 cycles before the first 1~7 days and after completing 13 cycles 7 days.Results: A total of 70 women were treated for 516 cycles, including 370 cycles in the experimental group and 146 cycles in the control group from July 9th, 2014 to March 1st, 2016. No pregnancies occurred with the two groups.One or more active pills were missed during 23(6.22%) cycles in the experimental group, 8.9% in higher dosage group.Three subjects missed ≥ 3 consecutive active pills in a cycle during the experimental group. 11 subjects discontinued this trial due to a variety of reasons. As compared to women using 0.02 mg EE preparations, those using the 0.03 mg EE preparations experienced considerably more frequent side effects. Abdominal distension was consistently higher frequency in the control group than in the experimental group(P ≤ 0.01).The incidence of side effects reduced with the extension of drug cycle in the first 10 cycles.Conclusion: Both groups have a good contraceptive effectiveness and acceptability. The experimental group has better tolerance than the control group by a lower incidence of side effects.Part II An assessment of the effect of lower dosage of Ethinylestradiol/Levonorgestrel on cycle control and the premenstrual syndromeObjectives: To evaluate the impact of 0.02 mg EE/0.10 mg LNG on cycle control and the premenstrual syndrome.Methods: Vaginal bleeding data from women who received either 0.02 mg EE/0.10 mg LNG(n = 25) or 0.03 mg EE/0.15 mg LNG(n = 11) were pooled and analysed over nine treatment cycles in accordance with the daily diary.Women who completed seven cycles in part I, in which the experimental group 34 cases and the control group 14 cases were selected to assess the impact of combined oral contraceptives on the physical, psychological and behavioral symptoms according to the scores of MDQ.Results: There was no amenorrhea in both groups.The menstrual cycle of test group shortened statistically significant(P < 0.05)after taking 2 and 8 medication cycles compared to no medication.There was not statistical difference in the control group.The menstrual duration of the control group is significantly shorter than the experimental group in cycle 5, but subjects could accept it.Spotting was more common among the lower dosage group, with a mean incidence of 4.44% compared to 2.02% in the higher dosage group.The incidence of unscheduled intracyclic bleeding was declining along with the extension of medication cycle and there was no statistically significant for the two treatment groups. No statistically significant was found between before and after treatment in the total scores of MDQ except the feelings of well-being,but the score of after treatment was lower than no medicine. Both groups had significant difference on inattention during the intermenstrual phase and the premenstrual phase after treatment(P < 0.05).Conclusion: Both groups could effectively control the menstrual cycle.The 0.02 mg EE/0.10 mg LNG group has higher percentage of irregular bleeding than the control group.In the aspect of the premenstrual syndrome,both groups had no significant effect on the MDQ after medicine and the control group may have more effective on improving inattention than the the test group.Part III Safety of the lower dosage of Ethinylestradiol/LevonorgestrelExperiment one Effects on lipid metabolism and blood clotting of the lower dosage of Ethinylestradiol/LevonorgestrelObjectives: To assess the effect of 0.02 mg EE/0.10 mg LNG on lipid metabolism and blood clotting.Methods: Datas from 48 volunteers were obtained(0.02 mg EE/0.10 mg LNG, n = 34; 0.03 mg EE/0.15 mg LNG, n = 14). Blood samples for the assessment of blood clotting, blood biochemical and blood routine were taken before treatment and in cycle 8.Samples were drawn following a 12 hour overnight fast.Weight, blood pressure and heart rate were taken during the pretreatment cycle, treatment cycles 2,5and 8(on cycle days 1 to 7).Results: No appreciable difference between the groups was found on basic vital signs,blood routine and blood biochemical.Levels of PT and APTT decreased significantly in both groups after 7 cycles compared with no medicine, and a significantly increases was seen in TT. However, mean levels of those parameters remained within the normal range in both treatment groups. No significant differences between the treatment groups for any of the laboratory parameters were found.Conclusion: It may not have the clinical significance of metabolism and blood coagulation after taking 0.02 mg EE/0.10 mg LNG 7 cycles.Experiment two Leptin and adiponectin evaluation in Ethinylestradiol/LevonorgestrelObjectives: The purpose of this study was to evaluate serum ADP, LEP levels and the correlation between adipokines and lipid profiles in women receiving 0.02 mg EE/0.10 mg LNG and 0.03 mg EE/0.15 mg LNG.Methods: Twenty eight healthy women who haven not taken COCs as the non-medication group. Twenty eight healthy women who visit in the same period of the menstrual cycle after 7 cycles were enrolled in this study(the medicine group 1, n = 20; the medicine group 2, n = 8). Fasting blood sample was collected from both groups for quantitative determination of serum LEP and ADP by ELISA.The determination of lipid metabolism was identical with experiment one of part III.Results: ADP showed significantly negative correlation with TC, LDL and Castelli index I.There was not significant difference in the medicine group 1, the medicine group 2 and the non-medication group.Conclusion: Adiponectin may be involved in regulation of lipid metabolism.The levels of LEP, ADP and ADP/LEP may not be influenced after taking EE/LNG 7 cycles.These observations must be extended in large scale study, the period of medication and controlled interference factors to confirm the effect of EE/LNG on adipokines.更多还原